PROJECT SUMMARY/ABSTRACT The prevalence of wheezing in preschool children has increased dramatically over the past three decades, resulting in a public health crisis. Nearly 50% of all preschool children experience at least one episode of wheezing before 6 years of age and up to 20% of all preschool children have recurrent wheezing episodes in early life associated with significant morbidity. Compared to older children, preschool children have twice the rate of emergency department visits, five times the rate of hospitalizations, and higher costs. Although preschool children with recurrent wheezing are a heterogeneous group with differing disease outcomes, there is a paucity of research in this age group and the associated biology of exacerbation and related outcomes in these children is not understood. Segmentation of preschool children with recurrent wheezing for the purpose of basic research is therefore one of the main research challenges in pediatric airway research today, since at present, the clinical course of preschool children with recurrent wheezing remains an enigma that is impossible to predict. Given our broad goal to advance personalized medicine for all children with respiratory disorders, we propose a 50-week phenotype-stratified cohort study (N=145) to determine whether phenotypic (i.e., clinical) and associated endotypic (i.e., biological) features predict wheeze exacerbation and related outcomes in preschool children age 12-59 months with a history of recurrent wheezing. We will pursue three aims: 1) determine whether wheezing phenotype predicts exacerbation occurrence (primary outcome), 2) determine whether wheezing phenotype predicts episode-free days (EFDs) and response to treatment with systemic corticosteroids (secondary outcomes), and 3) refine the prediction model for wheeze exacerbation with endotyping approaches (cytokines, metabolomics and immune cell studies). We hypothesize that a higher proportion of children with Type-2 (i.e., eosinophilic) inflammatory features will experience an exacerbation irrespective of viral status, and that these same children will have fewer EFDs, a higher proportion of virus- associated exacerbations, a greater response to treatment with systemic corticosteroids, and distinguishing cytokine profiles, plasma metabolomic biomarkers and markers of neutrophil and eosinophil activation and function. This project involves a multidisciplinary team with a history of collaboration and addresses a key area in the NINR Strategic Plan: to explore mechanisms underlying symptoms of illness and develop personalized treatments that address these mechanisms through symptom science research. The study population, preschool children with recurrent wheezing, is understudied and the knowledge gap is quite large. This project is ultimately expected to lay groundwork to: 1) refine knowledge of wheeze exacerbation and associated mechanisms, 2) improve clinical prediction of exacerbation and related outcomes, and 3) identify biomarkers of exacerbation that can be targeted in the future with personalized approaches, to reduce the high morbidity.